Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene. Prior studies in our laboratory demonstrated that mice with genetic disruption of the Type III isoform of neuregulin 1 (Nrg1tm1Lwr) have altered CNS structures and functions in ways reminiscent of phenotypes of schizophrenia. Schizophrenia is a devastating disorder affecting ~1% of people worldwide with largely unknown etiology and pathogenesis. Alterations in neural connectivity of cortical neurons have been implicated in schizophrenia based on a number of postmortem studies. In order to better understand schizophrenia-associated synaptic connectivity defects, I now propose to study the structural dynamics of synapses in Type III Nrg1 heterozygous (Nrg1 (+/-)) mice showing endophenotypes reminiscent of those observed in schizophrenia. I propose to use the thinned-skull technique together with two photon microscopy for long term in vivo imaging of dendritic spines in living animals. The current proposal will allow us to gain fundamental insights into changes in synaptic connectivity associated with schizophrenia thereby improving treatment methods. In addition, I propose to use Nrg1 (+/-) mice showing alterations in GABAergic interneurons and cognitive dysfunction to test the efficacy of a pharmacological modulator of the GABAergic receptors in ameliorating structural and behavioral deficits associated with cognitive impairments in schizophrenia. Analyses of the therapeutic potential will focus on the structural changes, i.e. spine turnover in vivo and spine density, and cognition-related behavioral assays. A better understanding of the mechanisms by which potential treatment interventions alter circuit components of cognition will provide insight into the neuronal mechanisms involved in the pathogenesis of schizophrenia and improve therapeutic methods. Furthermore, how interactions among schizophrenia risk genes contribute to the etiology of this complex disorder remain unclear. The candidate risk gene of interest is DISC1. In the current proposal, I will examine the role of Nrg1-DISC1 interaction in the regulation of neuroconnectivity by testing the hypothesis that DISC1 acts as a partner of Nrg1 in regulating spine development. In particular, I will assess the effects of disrupting DISC1 function on the spine density of cortical neurons of Nrg1 (+/-) mice. Proposed studies of gene-gene interaction should provide fundamental insights into pathophysiological mechanisms underlying schizophrenia with the possibility of developing double-hit animal models for testing the therapeutic potentials of novel agents. PUBLIC HEALTH RELEVANCE: Schizophrenia presents a serious public health problem affecting ~1% of people worldwide with largely unknown etiology and pathogenesis. Patients with schizophrenia show a broad range of cognitive dysfunction which is resistant to currently available antipsychotic drugs. Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene. In this project, I propose to study the dynamics of structural components of cortical synaptic connections, i.e. dendritic spines, in vivo in Type III neuregulin 1 heterozygous (Nrg1 (+/-)) mice showing phenotypes reminiscent of schizophrenia. In addition, I propose to use Nrg1 (+/-) mice to test the effects of two therapeutic approaches on ameliorating schizophrenia-associated structural changes and cognitive impairments. Furthermore, I will examine the role of Nrg1-DISC1 interaction in the regulation of neuroconnectivity by testing the hypothesis that DISC1 acts as a partner of Nrg1 in regulating spine development. The proposed study will allow us to gain fundamental insights into pathophysiological mechanisms underlying schizophrenia at structural and molecular levels and to better understand the therapeutic effects of potential treatment interventions thereby improving treatment strategies for neuropsychiatric disorders including schizophrenia.